Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.11.24 (mitogen-activated protein kinase)
 95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A novel amidine analogue of chlorambucil-N-(2-(4-(4-bis(2-chloroethyl)aminophenyl)butyryl)aminoethyl)-5-(4-amidinophenyl)-2-furancarboxamide hydrochloride (AB(1)) and the parent drug were compared for their effects on collagen and DNA biosynthesis in breast cancer MCF-7 cells. IC(50) values for chlorambucil and AB(1) for collagen biosynthesis were found to be about 33 and 13 microM, respectively. The greater potency of AB(1) to suppress collagen synthesis was found to be accompanied by a stronger compared with chlorambucil inhibition of prolidase activity and expression. The phenomenon was related to inhibition of beta(1)-integrin and IGF-I receptor-mediated signaling caused by this compound. The expression of beta(1)-integrin receptor, as well as Src, son of sevenless protein (SOS) and phosphorylated mitogen activated protein (MAP) kinases (MAPK), extracellular-signal-regulated kinase 1 (ERK(1)) and kinase 2 (ERK(2)) but not focal adhesion kinase pp125(FAK) (FAK), Shc, and Grb-2 was significantly decreased in cells incubated for 24 h with 10 microM AB(1) compared to the control, whereas in the same conditions chlorambucil did not evoke any changes in expression of all these signaling proteins, as shown by Western immunoblot analysis. Furthermore, AB(1) induced a stronger down-regulation of the expression of IGF-I receptor and evoked a higher antiproliferative effect. During 12 and 24 h of incubation AB(1) decreased DNA biosynthesis by about 33 % and 51 % of the control, whereas chlorambucil decreased it by about 19 % and 35 %, respectively. These data suggest that the amidine analogue of chlorambucil is a stronger inhibitor of protein and DNA synthesis in MCF-7 cells than is the parent drug.
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PMID:Amidine analogue of chlorambucil is a stronger inhibitor of protein and DNA synthesis in breast cancer MCF-7 cells than is the parent drug. 1517 51

The effects of oxidative stress on collagen and DNA biosynthesis, beta-galactosidase and prolidase activities, and the expression of prolidase, beta1-integrin receptor, FAK, IGF-IR and MAP-kinases (ERK1, ERK2) were evaluated in human dermal fibroblasts. Subconfluent cells were subjected to repetitive stresses with 30 microM t-BHP for 1 hour per day over the course of 5 days. It was found that oxidative stress induced the inhibition of collagen biosynthesis in these cells in a time-dependent manner. Exposure of the cells to 5 stresses contributed to a decrease in collagen and DNA biosynthesis to about 30% and 50% of the control values, respectively. Prolidase activity and expression were only suppressed in fibroblasts subjected to 1 and 3 stresses. In these cells prolidase activity was decreased by about 20%. As a result of 5 stresses, no further inhibition of prolidase activity occurred; however, expression of the enzyme was slightly increased, as demonstrated by Western blot analysis. It was found that these phenomena were neither related to the expression of beta1-integrin receptor nor to that of FAK. However, the exposure of the cells to 3 and 5 stresses contributed to a distinct decrease in IGF-IR and MAP-kinases (ERK1, ERK2) expression, which is probably responsible for the collagen biosynthesis inhibition.
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PMID:Oxidative stress induces IGF-I receptor signaling disturbances in cultured human dermal fibroblasts. A possible mechanism for collagen biosynthesis inhibition. 1564 87

Although hyaluronic acid (HA) has been used in the treatment of osteoarthritis for 30 years, the mechanism of its protective action on collagen metabolism disturbances in tissues during inflammation is not known. The present study was undertaken to evaluate the mechanism of Interleukin-1 (IL-1)-induced deregulation of collagen metabolism in cultured human skin fibroblast and the effect of HA on the process. In normal fibroblasts IL-1 strongly induced inhibition of collagen biosynthesis, while HA counteracted the process. The mechanism of this phenomenon was independent of prolidase activity, an enzyme that plays an important role in collagen biosynthesis at the post-translational level. Instead, IL-1 was found to inhibit the expression of insulin-like growth factor-I receptor (IGF-IR) and MAP kinases-ERK1 and ERK2, while HA was shown to counteract this process. Since insulin-like growth factor-I (IGF-I) is a most potent stimulator of collagen biosynthesis in fibroblasts the mechanism of IL-1-dependent inhibition of collagen biosynthesis may be related to inhibition of IGF-IR expression and signaling. The data suggest that hyaluronic acid protects collagen against IL-1-induced inhibition of biosynthesis of this protein in cultured human skin fibroblasts at the level of IGF-IR signaling.
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PMID:The effect of hyaluronic acid on interleukin-1-induced deregulation of collagen metabolism in cultured human skin fibroblasts. 1574 62

Prolidase [E.C. 3.4.13.9], a member of the matrix metalloproteinase (MMP) family, is a manganese-dependent cytosolic exopeptidase that cleaves imidodipeptides containing C-terminal proline or hydroxyproline. It plays an important role in collagen metabolism, matrix remodeling and cell growth. Nitric oxide (NO), a versatile signaling molecule, regulates many processes including collagen synthesis and matrix remodeling and, thereby, may modulate angiogenesis, tumor invasiveness, and metastasis. Thus, we considered that prolidase may be an important target of NO regulation. In our study, SIN I and DETA/NO were used as NO donors. Both donors increased prolidase activity in a time-dependent and dose-dependent manner. Prolidase activity increased not only with NO donors but also with endogenous NO in cells transfected with iNOS. The effect of iNOS was abolished by treatment with S-methylisothiourea (SMT), a selective inhibitor of iNOS. However, with either exogenous or endogenous sources of NO, the increase in prolidase activity was not accompanied by increased prolidase expression. Therefore, we suspected phosphorylation of prolidase as a potential mechanism regulating enzyme activation. We observed increased serine/threonine phosphorylation on prolidase protein in cells treated with NO donors and in cells transfected with iNOS. To determinate the pathways that may mediate prolidase induction by NO, we first used 8-Br-cGMP, a cGMP agonist, and found that 8-Br-cGMP strongly and rapidly stimulated prolidase activity accompanied by increased phosphorylation. Rp-8-Br-pCPT-cGMP, an inhibitor of cGMP, reduced NO donor-stimulated prolidase activity to control levels. To test whether the MAPK pathway is involved in this NO-dependent activation, we used an ERK1/2 inhibitor and found that it had no effect on prolidase activity increased by NO donors. These results demonstrate that NO stimulates prolidase activity by increasing serine/threonine phosphorylation through PKG-cGMP pathway, but independent of MAPK and suggest an interaction between inflammatory signaling pathways and regulation of the terminal step of matrix degradation.
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PMID:Nitric oxide regulates prolidase activity by serine/threonine phosphorylation. 1616 38

The potential role of butyrate to modulate cellular metabolism through integrin receptor led to evaluation of its effect on collagen biosynthesis in cultured fibroblasts. Confluent human dermal fibroblasts were treated with 2 mM and 4 mM of sodium butyrate (NaB) for 48 h. It was found that butyrate induced collagen biosynthesis and prolidase activity independently of alpha2beta1 integrin signaling. The expressions of both alpha2 and beta1 integrin subunits as well as integrin-induced activation of focal adhesion kinase (FAK) were not affected in the cells treated with NaB. Since insulin-like growth factor-I (IGF-I) is the most potent stimulator of collagen biosynthesis in fibroblasts, the effect of butyrate on IGF-I receptor (IGF-IR) expression was evaluated. It was found that the exposure of the cells to 4 mM butyrate contributed to a distinct increase in IGF-IR. It was accompanied by a parallel increase in the expression of Sos protein and MAP-kinases (ERK1, ERK2). The data suggests that butyrate-dependent stimulation of collagen biosynthesis in cultured human skin fibroblasts undergoes through IGF-IR signaling.
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PMID:Butyrate-induced collagen biosynthesis in cultured fibroblasts is independent on alpha2beta1 integrin signalling and undergoes through IGF-I receptor cascade. 1654 Nov 97

A novel amidine analogue of melphalan (AB4) was compared to its parent drug, melphalan in respect to cytotoxicity, DNA and collagen biosynthesis in MDA-MB-231 and MCF-7 human breast cancer cells. It was found that AB4 was more active inhibitor of DNA and collagen synthesis as well more cytotoxic agent than melphalan. The topoisomerase I/II inhibition assay indicated that AB4 is a potent catalytic inhibitor of topoisomerase II. Data from the ethidium displacement assay showed that AB4 intercalated into the minor-groove at AT sequences of DNA. The greater potency of AB4 to suppress collagen synthesis was found to be accompanied by a stronger inhibition of prolidase activity and expression compared to melphalan. The phenomenon was related to the inhibition of beta(1)-integrin and IGF-I receptor mediated signaling caused by AB4. The expression of beta(1)-integrin receptor, as well as Sos-1 and phosphorylated MAPK, ERK(1) and ERK(2) but not FAK, Shc, and Grb-2 was significantly decreased in cells incubated for 24h with 20 microM AB4 compared to the control, not treated cells, whereas in the same conditions melphalan did not evoke any changes in expression of all these signaling proteins, as shown by Western immunoblot analysis. These results indicate the amidine analogue of melphalan, AB4 represent multifunctional inhibitor of breast cancer cells growth and metabolism.
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PMID:Novel amidine analogue of melphalan as a specific multifunctional inhibitor of growth and metabolism of human breast cancer cells. 1673 Jun 67

The present study was undertaken to evaluate the mechanism of campthotecin (CPT)-induced deregulation of collagen metabolism in cultured human skin fibroblast. It has been found that CPT strongly induced inhibition of collagen biosynthesis. The mechanism of this phenomenon was found to be independent of prolidase activity, an enzyme that plays an important role in enhancement of collagen biosynthesis at post-translational level. In fact, the enzyme activity was found to be stimulated by CPT. Increase in the enzyme activity was accompanied by increase in the expression of beta(1) integrin receptor and some beta(1) integrin-dependent signalling proteins, Sos, MAPK (ERK(1), ERK(2)) and transcription factor NF-kappaB. Since activation of beta(1) integrin induces NF-kappaB that inhibits collagen gene transcription, therefore the mechanism of CPT-dependent inhibition of collagen biosynthesis may be related to beta(1) integrin-dependent stimulation of NF-kappaB. Supporting evidence comes from experiments showing that specific MEK/ERK inhibitor (UO126) inhibited CPT-induced up-regulation of prolidase activity while it had no effect on CPT-induced inhibition of collagen biosynthesis and activation of NF-kappaB. The data suggest that CPT induces inhibition of collagen biosynthesis in cultured human skin fibroblasts by stimulation of NF-kappaB signalling.
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PMID:Prolidase-independent mechanism of camptothecin-induced inhibition of collagen biosynthesis in cultured human skin fibroblasts. 1716 73

A number of novel proline-linked nitrosoureas (1-4) were synthesized and examined for cytotoxicity and influence on DNA and collagen biosynthesis in MDA-MB-231 and MCF-7 human breast cancer cells. Evaluation of the cytotoxicity of these compounds employing a MTT assay and inhibition of [(3)H]thymidine incorporation into DNA in both MDA-MB-231 and MCF-7 breast cancer cells demonstrated that compound 2, the most active of the series, proved to be only slightly less potent than carmustine. It has also been found that carmustine did not inhibit MCF&-7 cells prolidase activity, while compounds 1-4 significantly increased its activity, when used at 50-250 microM concentrations. Proline-linked nitrosoureas (1-4) also had lower ability to inhibit collagen biosynthesis in MCF-7 cells, compared to carmustine. The expression of beta(1)-integrin receptor and phosphorylated MAPK, ERK(1) and ERK(2) was significantly decreased in MCF-7 cells incubated for 24 h with 60 microM of compounds 2 and 4 compared to the control, untreated cells, whereas under the same conditions carmustine did not evoke any changes in expression of all these signaling proteins, as shown by Western immunoblot analysis. These results indicate the proline-linked nitrosoureas (1-4), represent multifunctional inhibitors of breast cancer cell growth and metabolism.
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PMID:Proline-linked nitrosoureas as prolidase-convertible prodrugs in human breast cancer cells. 1844 78

The effects of genistein, a soy isoflavone phytoestrogen and antioxidant, on collagen and DNA biosynthesis (measured by the 5-[3H]proline and the [3H]thymidine incorporation assays), prolidase activity (colorimetric method) and expression (determined by Western immunoblot) of the beta1-integrin receptor, focal adhesion kinase pp125(FAK) (FAK), Src, the insulin-like growth factor-I (IGF-I) receptor, Shc, growth-factor receptor-bound protein 2 (Grb2), son of sevenless protein (Sos) and phosphorylated mitogen activated protein (MAP) kinases, extracellular signal-regulated kinase 1 and 2 (ERK1/ERK2) were examined in normal human dermal fibroblasts (CRL-1474) exposed to oxidative stress. Subconfluent cells were subjected to repetitive stress with 30 microM t-butylhydroperoxide (t-BHP) in combination with 1-100 microM genistein for 1 h per day over the course of 5 days. Also, the cells were treated with t-BHP alone or with t-BHP in combination with 1-100 microM ascorbate. It was found that genistein at 1 microM counteracted the inhibition of collagen biosynthesis evoked by t-BHP in fibroblasts, more effectively than ascorbate at the same concentration. At 10 microM, genistein exerted significantly diminished protective effect on collagen biosynthesis in fibroblasts, while at 100 microM it induced inhibition of this process. The protective effect of genistein on collagen biosynthesis was not related to modulation of prolidase activity or the expression of the beta1-integrin receptor, FAK, Src or Grb2. It was found that genistein, at 1 microM, diminished t-BHP-induced down-regulation of the IGF-I receptor, Shc, Sos and phosphorylated ERK1/ERK2 expression in fibroblasts. Simultaneously, genistein counteracted the antiproliferative activity of the oxidant. These results suggest that the mechanism of the protective effect of genistein on collagen biosynthesis in t-BHP-treated fibroblasts may be due to prevention of disturbances in the IGF-I receptor-mediated, ERK1/ERK2-associated signaling pathway evoked by the oxidant.
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PMID:Nutritional concentration of genistein protects human dermal fibroblasts from oxidative stress-induced collagen biosynthesis inhibition through IGF-I receptor-mediated signaling. 1866 26

The data showing that butyrate may play an important role in cellular metabolism led us to study its effect on collagen biosynthesis in cultured fibroblasts. Since insulin-like growth factor-I (IGF-I) is the most potent stimulator of collagen biosynthesis in fibroblasts, the effect of butyrate on IGF-I receptor (IGF-IR) expression was evaluated. Confluent human dermal fibroblasts were treated with millimolar concentrations of sodium butyrate (NaB) for 48 hours. It was found that butyrate induced collagen biosynthesis and prolidase activity. It was found that the exposure of the cells to 4 mM butyrate contributed to a distinct increase in IGF-IR. It was accompanied by a parallel increase in the expression of Sos protein and MAP-kinases (ERK1, ERK2). It was found that the MEK inhibitor decreased collagen biosynthesis and expression of MAP-kinases (ERK1, ERK2), while NaB counteracted the process. The data suggests that butyrate-dependent stimulation of collagen biosynthesis in cultured human skin fibroblasts undergoes through IGF-IR signaling.
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PMID:The mechanism of butyrate-induced collagen biosynthesis in cultured fibroblasts. 1964 22


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